The establishment and maintenance of pregnancy require appropriate development of a specialized maternal tissue, referred to as decidua. Decidual cells arise from uterine stroma via the actions of progesterone, form intimate relationships with placental structures, and facilitate the development of the embryo. The actions of progesterone are mediated, in part, through activation of the transcriptional regulator CCAAT/enhancer binding protein (3 (C/EBP[unreadable]). Among the important functions of decidual cells are their hormone/cytokine producing capabilities. Hormone/cytokines related to prolactin (PRL) are prominent decidual cell secretory proteins and include decidual prolactin-related protein (dPRP). The uteroplacental PRL family has been implicated in the regulation of uterine inflammatory cell responses accompanying pregnancy. We propose that dPRP modulates intrauterine responses to inflammation/physiological stressors, including inhibiting decidual cell stress and preserving vascular integrity. Dysregulation of dPRP results in decidual cell stress (including upregulation of CHOP) and vascular instability. CHOP is a known inhibitor of C/EBP[unreadable] actions, and its activation potentially compromises decidual cell function. Disruptions in decidual cell function and in vascular integrity increase susceptibility to pregnancy failure. In this research project, we plan to investigate the regulation of decidual cell adaptations to physiological stressors. In Specific Aim No. 1 we investigate factors impacting and mediating decidual adaptations to physiological stressors. Specific Aim No. 2 assesses the role of dPRP and human PRL in the regulation of adaptations to physiological stressors. The third Aim investigates the role of CHOP in the dysregulation of decidual cell function following exposure to physiological stressors. Each Aim is entirely independent and will be started at the beginning of year one of the grant period and will proceed in parallel through the end of the proposed grant period. The planned research utilizes cellular and molecular and in vitro and in vivo strategies. Data derived from the proposed experimentation will improve our understanding of the nature of decidual cell signaling and the role of the decidual PRL family in the regulation of viviparity. These findings will provide considerable insight into the etiology of developmental disorders associated with pregnancy failure and will also have important ramifications on our understanding of adaptations to physiological stressors.